Tyrosine hydroxylase deficiency

Tyrosine hydroxylase (TH) deficiency is a disorder that primarily affects movement. There are three forms of tyrosine hydroxylase deficiency, and they are categorized based on the severity of their symptoms and their response to treatment. The three forms range in severity from mild to severe.

For those with the mild form of tyrosine hydroxylase deficiency (also called TH-deficient dopa-responsive dystonia), symptoms usually appear during childhood. Affected individuals may have difficulties walking and running, which can sometimes lead to falls. Some people with the disorder may walk on their toes because of stiffness in the leg muscles. Additional signs and symptoms may include involuntary muscle contractions (dystonia) that lead to abnormal repetitive movements in the legs, tremor when holding a position (postural tremor), or involuntary upward-rolling movements of the eyes. Symptoms tend to worsen later in the day for some people with TH-deficient dopa-responsive dystonia. Affected individuals may experience more pronounced movement difficulties as they age, but these symptoms almost always get better with medical treatment.

The more severe forms of tyrosine hydroxylase deficiency are often called TH-deficient infantile parkinsonism or TH-deficient progressive infantile encephalopathy. These forms of the disorder appear soon after birth and are more difficult to treat.

Signs and symptoms of TH-deficient infantile parkinsonism typically begin in the first year of life. Affected infants often have delayed development of motor skills such as sitting unsupported or reaching for a toy. Some signs and symptoms may resemble those seen in people with Parkinson disease: stiffness of the muscles in the arms and legs, slow or diminished movements (hypokinesia), and tremors. Additional signs and symptoms may include droopy eyelids (ptosis), involuntary upward-rolling eye movements, and intellectual disabilities. People with TH-deficient infantile parkinsonism may respond to treatment, though treatment may not work right away and may not resolve all of the symptoms of the condition.

The most severe form of tyrosine hydroxylase deficiency (also called TH-deficient progressive infantile encephalopathy) is characterized by brain dysfunction that leads to profound physical and intellectual disabilities. Signs and symptoms typically begin in the first six months of life. Babies with this form of tyrosine hydroxylase deficiency often have feeding difficulties and delayed growth. Additional features include hypokinesia and abnormal eye movements. This form of tyrosine hydroxylase deficiency is difficult to treat, as affected infants tend to be more likely to experience harmful side effects from the medicine.

Though the exact prevalence is not known, more than 100 individuals with tyrosine hydroxylase deficiency have been reported in the literature. 

Many different variants (also called mutations) in the TH gene cause tyrosine hydroxylase deficiency. The TH gene provides instructions for making the enzyme tyrosine hydroxylase, which is important for normal functioning of the nervous system.

Tyrosine hydroxylase takes part in the pathway that produces a group of chemical messengers called catecholamines. Tyrosine hydroxylase helps convert the protein building block (amino acid) tyrosine to a catecholamine called dopamine. Dopamine transmits signals to help the brain control physical movement and mood. Other catecholamines called norepinephrine and epinephrine are produced from dopamine. Norepinephrine and epinephrine are involved in the autonomic nervous system, which controls involuntary body processes such as the regulation of blood pressure and body temperature.

Variants in the TH gene reduce the activity of the tyrosine hydroxylase enzyme. As a result, the body produces less dopamine, norepinephrine and epinephrine. These catecholamines are necessary for normal nervous system function, and changes in their levels likely contribute to the abnormal movements and other neurological problems seen in people with tyrosine hydroxylase deficiency. Researchers are still trying to understand why some individuals have more severe signs and symptoms than others. 

Genetic Testing Information

• Genetic Testing Registry: Autosomal recessive DOPA responsive dystonia
• Genetic Testing Registry: Tyrosine hydroxylase deficiency

Genetic and Rare Diseases Information Center

• Autosomal recessive dopa-responsive dystonia

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• SEGAWA SYNDROME, AUTOSOMAL RECESSIVE

Scientific Articles on PubMed

• PubMed

• Furukawa Y, Kish S. Tyrosine Hydroxylase Deficiency. 2008 Feb 8 [updated 2017 May 11]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK1437/ Citation on PubMed
• Furukawa Y, Kish SJ, Fahn S. Dopa-responsive dystonia due to mild tyrosine hydroxylase deficiency. Ann Neurol. 2004 Jan;55(1):147-8. doi: 10.1002/ana.10820. No abstract available. Citation on PubMed
• Furukawa Y. Update on dopa-responsive dystonia: locus heterogeneity and biochemical features. Adv Neurol. 2004;94:127-38. No abstract available. Citation on PubMed
• Hoffmann GF, Assmann B, Brautigam C, Dionisi-Vici C, Haussler M, de Klerk JB, Naumann M, Steenbergen-Spanjers GC, Strassburg HM, Wevers RA. Tyrosine hydroxylase deficiency causes progressive encephalopathy and dopa-nonresponsive dystonia. Ann Neurol. 2003;54 Suppl 6:S56-65. doi: 10.1002/ana.10632. Citation on PubMed
• Pearl PL, Capp PK, Novotny EJ, Gibson KM. Inherited disorders of neurotransmitters in children and adults. Clin Biochem. 2005 Dec;38(12):1051-8. doi: 10.1016/j.clinbiochem.2005.09.012. Epub 2005 Nov 18. Citation on PubMed
• Pearl PL, Taylor JL, Trzcinski S, Sokohl A. The pediatric neurotransmitter disorders. J Child Neurol. 2007 May;22(5):606-16. doi: 10.1177/0883073807302619. Citation on PubMed
• Verbeek MM, Steenbergen-Spanjers GC, Willemsen MA, Hol FA, Smeitink J, Seeger J, Grattan-Smith P, Ryan MM, Hoffmann GF, Donati MA, Blau N, Wevers RA. Mutations in the cyclic adenosine monophosphate response element of the tyrosine hydroxylase gene. Ann Neurol. 2007 Oct;62(4):422-6. doi: 10.1002/ana.21199. Citation on PubMed